Diabetes was recorded long before. It is a metabolic disease characterized by chronic hyperglycemia because of absolute or relative lack of insulin in the human body resulting in increased concentrations of glucose in the blood and dramatic glucose discharges in urine, along with sugar, lipid and protein metabolic disorder and physiologically expresses increased drinking, increased urining, increased eating, weight loss, dizziness, weakness and other symptoms.
Persistent or uncontrolled hyperglycemia is associated with increased morbidity and mortality. Often abnormal glucose homeostasis is associated directly or indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Patients with type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, such as coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy etc. Therefore, therapeutical control of glucose homeostasis, lipid metabolism, hypertension and the like is very important for the clinical treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes, i.e., insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin which is the hormone that regulates glucose utilization. In type 2 diabetes, i.e., noninsulin-dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects. However, these patients have developed a resistance to the insulin which has stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues such as muscle, liver and 25 adipose tissues, and the plasma insulin levels, even if elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not primarily due to a diminished number of insulin receptors but also to a post-insulin receptor binding defect that is not yet understood so far. This resistance to insulin responsiveness results in insufficient insulin-dependent activation of glucose uptake, oxidation and storage in muscle, and inadequate repression of lipolysis in adipose tissue and regulation of glucose production and secretion in the liver.
Dipeptidyl peptidase-IV (DPP-IV) is a serine protease which cleaves N-terminal dipeptides from a polypeptide containing a proline residue at the penultimate position. Although the biological role of DPP-IV in mammalian systems has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, adhesion and invasion of cancer cells to the endothelium and the entry of HIV into lymphoid cells (WO98/19998).
Recently, it is discovered that DPP-IV is responsible for preventing glucagon-like peptide-1 (GLP-1) secretion. More particularly, DPP-IV cleaves the N-terminal His-Ala dipeptide of GLP-1, thus degrading the active GLP-1(7-36)NH2 to the inactive GLP-1(9-36)NH2 (Endocrinology, 1999, 140: 5356-5363). Under physiological conditions, the half-life of the whole GLP-1 in blood circulation is short. The inactive metabolite of GLP-1 after degradation by DPP-IV can bind with GLP-1 receptors, thus antagonize active GLP-1, and shorten the physiological responses to GLP-1. However, DPP-IV inhibitors can protect endogenous or even exogenous GLP-1 from being inactivated, and thus significantly increase GLP-1 bioactivity (5- to 10-fold). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, DPP-IV inhibition appears to represent an attractive approach for treating non-insulin-dependent diabetes mellitus (NIDDM) (U.S. Pat. No. 6,110,949).
Although some DPP-IV inhibitors have been disclosed, there is no long effective drug at present. Improved DPP-IV inhibitors are still needed.
The purpose of the present invention is to provide a series of compounds which have DPP-IV inhibition activity and can be used for the treatment of diabetes or similar disease, or used as palliative drugs.
The application PCT/CN2008/001936 submitted by the applicant of the present invention on 4 Jan. 2009 described a novel tetrahydro-imidazo[1,5-a]pyrazine derivatives and their uses as DPP-IV inhibitor. The example 10 disclosed in it was (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid hydrochloride which was confirmed to have an excellent inhibition activity against DPP-IV according to the test. Therefore this application was whole incorporated here as reference.
The other purpose of the present invention is to provide the pharmaceutically acceptable salts of compounds represented by formula (I) and their compositions to improve their solubility, bioavailability, hypoglycemic activity and pharmacokinetics.